Project Summary Alzheimer?s disease is the most common age-related neurodegenerative disease, and there is a clear need to develop effective approaches to treat or prevent the cognitive impairment that is the prominent symptom of this disease. Neuroinflammation and mitochondrial impairments have been implicated in the pathogenesis of Alzheimer?s disease, and ketogenic diets have been reported to decrease inflammation and enhance mitochondrial function. This has led to speculation that ketogenic diets may provide an effective approach to treat Alzheimer?s disease. In support of this idea, short-term (?3 months) studies have shown that ketogenic diets improve motor function in mouse models of Alzheimer?s disease. However, memory was not improved with this diet, perhaps because the impact of the ketogenic diet was blunted by the ad libitum feeding approach used in these studies. There is growing appreciation that physiological response to a high fat diet is likely dependent on level of energy intake. Ketogenic diets are inherently high in fat and ad libitum feeding of a high fat diet induces a metabolic stress that may impair cognitive function. To investigate the physiological impact of these diets independent of differences in energy intake, we fed mice a ketogenic diet in isocaloric amounts to a control diet and found that the ketogenic diet increased life span and preserved memory and motor function with advanced age. It remains to be determined whether this feeding approach, which produces sustained ketosis, would also improve memory in rodent models of Alzheimer?s disease. Calorie restriction and intermittent fasting, which produce intermittent periods of ketosis, have also been reported to mitigate cognitive impairments in mouse models of Alzheimer?s disease. This raises the possibility that ketosis does not need to be continuous to have a beneficial impact on memory, which if true, would provide a lifestyle change more likely to be adopted by at-risk individuals. Sustained or intermittent increases in blood ketone levels with consumption of a ketogenic diet may be particularly beneficial if they lessen inflammation. Thus, we hypothesize that isocaloric ketogenic diet feeding approaches that produce either sustained or intermittent ketosis will decrease neuroinflammation and delay the onset or lessen the severity of disease progression in the TgF344-AD rat model of Alzheimer?s disease. We propose two specific aims to test this hypothesis: 1) determine if an isocaloric ketogenic diet feeding approach slows disease progression in the TgF344-AD rat; 2) determine if intermittent feeding of a ketogenic diet is sufficient to delay the onset or lessen the severity of memory and motor deficits in the TgF344-AD rat. These studies will take an important step toward determining if ketogenic diet approaches provide a viable strategy to treat or prevent Alzheimer?s disease.